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Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy.

ABSTRACT: Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the detection of desmoglein 2 auto-antibodies in AC patients. Using two mouse strains producing either a mutant desmoglein 2 or lacking desmoglein 2 in cardiomyocytes, we test the hypothesis that inflammation is a major component of disease pathogenesis. We show that multifocal cardiomyocyte necrosis initiates a neutrophil-dominated inflammatory response, which also involves macrophages and T cells. Increased expression of Ccl2/Ccr2, Ccl3/Ccr5, and Cxcl5/Cxcr2 mRNA reflects the observed immune cell recruitment. During the ensuing acute disease phase, Mmp12+ and Spp1+ macrophages and T cells accumulate in scars, which mature from cell- to collagen-rich. The expression of Cx3cl1/Cx3cr1, Ccl2/Ccr2, and Cxcl10/Cxcr3 dominates this disease phase. We furthermore find that during chronic disease progression macrophages and T cells persist within mature scars and are present in expanding interstitial fibrosis. Ccl12 and Cx3cl1 are predominant chemokines in this disease phase. Together, our observations provide strong evidence that specific immune cell populations and chemokine expression profiles modulate inflammatory and repair processes throughout AC progression.

SUBMITTER: Lubos N

PROVIDER: S-EPMC7289786 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy.

Lubos Nadine N van der Gaag Svenja S Gerçek Muhammed M Kant Sebastian S Leube Rudolf E RE Krusche Claudia A CA

Basic research in cardiology 20200612 4

Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the ...[more]

PMID: 32529556

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Project description:Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.

Dataset Information

Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy.

Publications

Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy.

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